Hormonal therapy is currently used for the treatment of estrogen-sensitive breast cancers. As the majority of breast cancers are initially estrogen-dependent, with approximately 55% in premenopausal women and 75% in post-menopausal women, this therapy efficiently blocks the stimulating effect of estrogens in breast cancer cells.1 Selective estrogen receptor modulator (SERM) compounds, such as tamoxifen and raloxifene, are presently used to treat breast cancer.2 In breast tissues, SERMs effectively block the activation of estrogen receptor alpha (ERα) by endogenous ligands and prevent the transcription of genes mediated by estrogen response elements (EREs).3 This class of compounds possesses the particularity of having tissue specific effects on ERα, resulting in antagonist activity in breast and uterus tissues and agonist activity in bone tissues. Although tamoxifen and raloxifene possess the desired SERM activity, they also increase the risk of venous thromboembolism.4,5 There remains a need for SERM compounds which exhibit fewer side effects.6 
Inhibition of steroid sulfatase (STS) is a therapeutic approach for the treatment of estrogen-dependent breast cancers. In this regard, various types of STS inhibitors have been developed during the past years.7-9 STS is an enzyme that converts inactive sulfated steroids, mainly pregnenolone sulfate (PREGS), estrone sulfate (E1S) and dehydroepiandrosterone sulfate (DHEAS), into unconjugated hormones. This is outlined in FIG. 1.10 E1S and DHEAS are particularly abundant in circulation and act as reservoir of steroid precursors.11 It is also known that STS activity in breast cancer tumors is much higher than aromatase, activity and that in situ formation of estrone (E1) and estradiol (E2) is mainly done via the STS pathway rather than the aromatase pathway.12-14 Therefore blocking STS could prevent estrogen-sensitive carcinomas from transforming sulfated steroids into potent estrogens, mainly estrone (E1), estradiol (E2) and 5-androstenediol (5-diol).
The dual blockade of ERα and STS to reach a maximum estrogen blockade for the treatment of estrogen receptor-positive (ER+) breast cancers represents an interesting therapeutic approach. However, the maximum estrogen blockade obtained by this approach induces an estrogen depletion condition that could provoke undesirable side effects such as osteoporosis.15 
An approach investigated in our laboratory relates to the design and development of dual-action compounds, i.e., compounds that are inhibitors of STS and that also possess estrogen modulator activity. More specifically, our approach aims at developing a non-steroidal sulfamoylated inhibitor of the enzyme STS that also possesses, among others, a selective estrogen receptor modulator (SERM) activity such as to attenuate a potential problem related to estrogen depletion induced by the inhibition of STS.16 
There is a need for compounds that are inhibitors of STS and that also possess SERM capacity. Advantageously, such compounds may also present other biological activities of interest. For example, such compounds may have the ability to increase alkaline phosphate (ALP) activity.
Turning to androgen-dependent cancers such as prostate cancer:
Steroid Sulfatase (STS) and Prostate Cancer
Steroid hormones play an important role in the growth of androgen-sensitive cancers.17,18 This type of cancer represents approximately 30% of all cancers in men in Canada.19 The blockade of the action of the active steroids on the androgen receptor has allowed for the development of new therapies. The use of these therapies which are more specific and generally better tolerated than chemotherapy, has led to interesting results in the treatment of prostate cancer (use of an antiandrogen with a lutheinizing hormone releasing hormone (LHRH) agonist).20,21 For an optimal use of this approach, it is important to completely block hormonal stimulation such as to avoid any subsequent recovery in the growth of tumors. Until now, it has merely been a partial blockade of hormone action, which has not allowed for a full exploitation of this approach. Indeed, the competitive blockade of hormone receptors by a pure antihormone is not optimal, since it can cause the accumulation of active steroids that compete for the binding to the receptor, thereby reducing the effectiveness of the blockade. In addition, we must take into account the ability of peripheral tissues to synthesize in large quantities, the active hormones from dehydroepiandrosterone sulfate (DHEAS) and also the ability of tumors to synthesize de novo active androgens.22 It is increasingly evident that a maximum blockade of the hormonal action will be ultimately reached by the combined effect of antihormone (receptor blockade) and an effective enzyme inhibitor (blocking of steroidogenesis).
Removal of endocrine glands responsible for steroidogenesis has been and is still regarded as a way of blocking the production of steroid hormones. This surgical approach has however the disadvantage of being an irreversible process that is not without side effects for the patient physically and psychologically. For this reason, the development of medical strategies that are reversible was encouraged, particularly chemical blocking. The strategy used to produce a chemical or medical castration is to block the release of gonadotropins by the pituitary gland, and thus stop the formation of steroidal hormones.23,24 Although chemical castration is effective, it still leaves significant portion of residual steroids of adrenal origin. In addition, since the affinity of antiandrogens used to block the androgen receptor is quite low, receptor blockade is not complete. Other means should be considered that completely eliminate the production of steroid hormones involved in the stimulation of hormone-sensitive cancers. Selective blocking of an enzyme involved in steroidogenesis is an interesting approach as it would then be possible to block the formation of a class of hormones produced locally by intracrinology without harming others, resulting in reduced side effects for the patient. This approach, which consists of blocking the biosynthesis of active steroids, has been successful for the treatment of advanced prostate cancers—an inhibitor of CYP17A1 (17α-hydroxylase/17,20-lyase) such as abiraterone acetate was used.25 
Steroid sulfatase (STS) is also a key enzyme in the androgen biosynthesis, accordingly also represents a target. Sulfatases are a group of enzymes that catalyze the conversion of sulfate compounds (R—OSO3H) into corresponding unconjugated compounds (R—OH).26 Nine members of the large family of sulfatases have been isolated from humans and their corresponding gene identified.27 Of these families, STS catalyzes the hydrolysis of 3-hydroxysteroid sulfate such as dehydroepiandrosterone sulfate (DHEAS), estrone sulfate (E1S) and pregnenolone sulfate (PREGS), which are inactive on their respective receptor, into their corresponding free steroids, DHEA, E1 and PREG, which are assets and/or available for steroidogenesis (FIG. 2).28 Given the large amounts of DHEAS which is a precursor of androgens in peripheral tissues targeted, it is important to monitor the activity of the STS.22 Potentially, there are several advantages of using an STS inhibitor in the context of prostate cancer. Firstly, it would prevent the intracrine transformation of abundant precursor DHEAS produced by the adrenal androgenic hormones in peripheral tissues such as the prostate and seminal vesicles. Also, it would prevent the transformation of the intratumoral androgen DHEAS which is active in androgen-sensitive tumors of the prostate or metastasis.22 Furthermore, while androgens have generally been considered to be the main stimulus for the development and growth of tumors of the prostate, estrogens are now being pointed out to be potentially a significant actor in the progression of the disease.29-32 High concentrations of E1S have been found in prostate cancer cells, and E1S has been found to be a prognosis marker of tumor aggressiveness in prostate cancer.33 Since STS is involved in the conversion of E1S to estradiol (E2), the most potent estrogen, an STS inhibitor could also be efficient to prevent the estrogenic stimulation of the tumors. Recently, a Phase I clinical trial using an STS inhibitor (irosutat) in patients with castrate-resistant prostate cancer has been initiated in North America.34 
Estrogen Receptor, SERM and Prostate Cancer
Estrogen receptors (ERs) are members of a nuclear receptor superfamily of ligand activated transcription factors.35 To date, two different ERs (ERα and ERβ) have been described and shown to be critically and differentially involved in the regulation of the normal function of reproductive tissues.36,37 In normal prostate tissues, the ERα is expressed specifically in the stromal cells and the ERβ in the epithelial cells. However, in prostate cancer cells, both ERα and ERβ are expressed in a similar proportion.39 There is currently increasing evidence on the role played by estrogens in prostate cancer initiation and progression.31,40 Estrogens are involved in the activation or inhibition of key proteins like TGFα,41 insulin growth like factor,42 TGFβ,42 calmodulin,43 protein kinase C,44 p21wasfll/cipl CIPI45 and TMPRSS2:ERG.46 Thus it appears that, in addition to androgens, estrogens are also fundamentally involved in the regulation of malignant growth in the prostate.47,48 
A selective estrogen receptor modulator (SERM) interacts with estrogen receptors as agonist or antagonist depending on the target tissue. Currently available SERM compounds are used to treat and prevent breast cancer and osteoporosis, to treat ovulatory dysfunction in women, and for contraception.49 However, the literature suggests that an SERM may also be used to treat prostate cancer.38,47,48 In recent studies, the SERM toromifene was found to suppress the development of high grade of prostatic intraperithelial neoplasia (PIN) and to decrease the incidence of adenocarcinoma in the prostate transgenic mouse model showing the potential of a SERM compound to treat prostate cancer.50,51 All these data point toward an important role for estrogen in prostate cancer, and also indicate that a SERM compound may be of great interest in the management and treatment of prostate cancer.
ISTS-SERM and Prostate Cancer
Obtaining a compound that is inhibitor of STS (ISTS) and that also possess SERM-like behavior may be greatly advantageous given that the biosynthesis of active hormones (androgen from DHEAS and estrogen from E1S respectively) as well as the estrogen receptor (ERα) will be simultaneously blocked (FIG. 3). A synergical effect due to the concerted actions of an ISTS-SERM compound may induce an increased apoptotic rate in prostate cancer cells as it has been observed in a recent study involving a combined antiandrogen and SERM for targeting the blockade of both androgen receptor (AR) and estrogen receptor (ER).52 
Furthermore, as an important complementary effect, an ISTS-SERM compound will also prevent important side effects related to androgen deprivation. Indeed, complications stemming from the blockade of the formation of androgens (osteoporosis, hot flashes, loss of sexual desire, impotence, breast tenderness) observed with androgen deprivation therapies (ex: LHRH agonist/antagonist or antiandrogen) often discourage men to pursuing and fully complete their long-term treatment against recurrence of prostate cancer.53 Supporting this potential adjuvant role of an ISTS-SERM compound, a recent study has shown that the SERM toromifene reduces the fracture risk in men receiving androgen deprivation therapy for prostate cancer.54 
Endometrosis and Other Medical Conditions
Endometriosis is another medical condition that may be treated using compounds that are inhibitors of STS and that possess SERM capacity.79,80 Other medical conditions include for example osteoporosis and benign prostatic hyperplasia.
In the development of treatments for estrogen- and androgen-dependent diseases, there is a need for compounds that are inhibitors of STS and that possess SERM capacity. Advantageously, such compounds may also present other biological activities of interest. For example, they may increase alkaline phosphate (ALP) activity.